(3R)-4-{[(1S)-2-Methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoic acid (1),
a prodrug of the GABAB agonist, R-baclofen((±)-4-amino-3-(4-chlorophenyl)butanoic acid), exhibits high bioavailability as R-baclofen when dosed either orally or directly into the colon of a mammal (Gallop et al., U.S. Pat. Nos. 7,109,239 and 7,227,028; and Lal et al., J Pharmacology Experimental Therapeutics 2009, 330(3), 911-921).
The high R-baclofen oral bioavailability following administration of compound (1) favors the use of compound (1) in oral dosage forms, including sustained-release oral dosage forms, and the use of such oral dosage forms for treating diseases such as spasticity and gastro-esophageal reflux disease (van Herwaarden et al., Aliment. Pharmacol. Ther. 2002, 16(9), 1655-62; Ciccaglione and Marzio, Gut 2003, 52(4), 464-70; Andrews et al., U.S. Pat. No. 6,117,908; and Fara et al., WO 02/096404); in promoting alcohol abstinence in alcoholics (Gessa et al., WO 01/26638); in promoting smoking cessation (Gessa et al., WO 01/08675); in reducing addiction liability of narcotic agents (Robson et al., U.S. Pat. No. 4,126,684); in the treatment of emesis (Bountra et al., U.S. Pat. No. 5,719,185); as an anti-tussive for the treatment of cough (Kreutner et al., U.S. Pat. No. 5,006,560); as well as for treating neuropathic and musculoskeletal pain (Benson et al., US 2009/0118365), urinary incontinence (Wun and Wustrow, U.S. Provisional Application Ser. No. 61/309,336, filed Mar. 1, 2010), movement disorders such as dystonia and hiccups; peripheral nerve disorders such as muscle stimulation disorders; spinal cord disorders such as spastic paraparesis; cranial nerve disorders such as glossopharyngeal neuralgia and trigeminal neuralgia; multiple sclerosis; and cerebral palsy.
The synthesis of compound (1) is described by Gallop et al., U.S. Pat. No. 7,109,239; Gallop et al., U.S. Pat. No. 7,227,028; Gallop et al., US 2009/0192325; Raillard et al., U.S. application Ser. No., 12/537,798 filed Aug. 7, 2009; and Raillard et al., U.S. application Ser. No. 12/537,764 filed Aug. 7, 2009, each of which is incorporated herein by reference in its entirety.
Oral dosage forms comprising compound (1) are disclosed in Kidney et al., US 2008/0206332; and Sastry et al., US 2009/0197958. Kidney et al. disclose sustained release tablet dosage forms comprising compound (1) and a release rate-controlling polymer prepared using high shear wet granulation. Sastry et al. disclose sustained release particulate dosage forms comprising compound (1).
In the direct compression tablet manufacturing process, tablet components are combined by dry blending and the resulting dry blend is subsequently combined into tablets with punch tooling on a rotary tablet press. Previous matrix tablet formulations of compound (1) required the use of organic solvents such as alcohols during the high shear wet granulation process in order to form free-flowing granulations (Kidney et al., US 2008/0206332). Free-flowing granulations are required in manufacturing processes to maintain acceptable weight control on rotary tablet presses. Solvents used in the high shear wet granulation process must subsequently be removed to acceptable levels by drying at elevated temperature, which increases manufacturing costs and slows the production rate.